Large-scale meta-analysis of mutations identified in panels of breast/ovarian cancer-related genes — Providing evidence of cancer predisposition genes

Suszyńska, Malwina; Klonowska, Katarzyna; Jasinska, Anna J.; Kozlowski, Piotr

doi:10.1016/j.ygyno.2019.01.027

Cited by 52 publications

(70 citation statements)

References 39 publications

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“…Ramus et al described a relative risk associated with protein truncating variants in BRIP1 of 11.2 (95% CI 3.2–34.1), with an estimated cumulative risk of 5.8% (95% CI 3.6–9.1%) by the age of 80 years [ 11 ] ( Table 2 ). The association between protein truncating variants in BRIP1 and risk of ovarian cancer has been confirmed in other analyses (associated risks ranged from 2.6 to 6.4 [ 27 , 28 , 29 , 35 , 45 ]) ( Table 2 and Table 3 ). The frequency of protein truncating variants in population-based studies, separated by ovarian cancer histotypes are given in Table 2 , and the frequency in the other retrospective studies, mostly family studies or with women referred to clinical testing, are given in Table 3 .…”

Section: Protein Truncating Variants In Confirmed Susceptibility Gsupporting

confidence: 62%

“…Early studies of cases selected for a family history of breast or ovarian cancer found that 24–76% had deleterious variants in BRCA1 and 1–17% had deleterious variants in BRCA2 [ 17 ]. Recent studies using clinical testing laboratory data have reported the prevalence of BRCA1/2 pathogenic variants in 5020 and 7489 cases from the USA [ 26 , 27 ], 4409 cases from France [ 28 ], and 3230 cases from a meta-analysis of 48 multi-gene panel testing-based studies [ 29 ]. In these studies, the frequency of germline pathogenic variants in BRCA1 in ovarian cancer cases were 5.1%, 3.6%, 3.7%, and 8.6%, respectively, and 3.9%, 3.3%, 4.0%, and 4.5% in BRCA2 [ 26 , 27 , 28 , 29 ].…”

Section: Protein Truncating Variants In Confirmed Susceptibility Gmentioning

confidence: 99%

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Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer

Pavanello

Chan

Ariff

et al. 2020

Cancers

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A family history of ovarian or breast cancer is the strongest risk factor for epithelial ovarian cancer (EOC). Germline deleterious variants in the BRCA1 and BRCA2 genes confer EOC risks by age 80, of 44% and 17% respectively. The mismatch repair genes, particularly MSH2 and MSH6, are also EOC susceptibility genes. Several other DNA repair genes, BRIP1, RAD51C, RAD51D, and PALB2, have been identified as moderate risk EOC genes. EOC has five main histotypes; high-grade serous (HGS), low-grade serous (LGS), clear cell (CCC), endometrioid (END), and mucinous (MUC). This review examines the current understanding of the contribution of rare genetic variants to EOC, focussing on providing frequency data for each histotype. We provide an overview of frequency and risk for pathogenic variants in the known susceptibility genes as well as other proposed genes. We also describe the progress to-date to understand the role of missense variants and the different breast and ovarian cancer risks for each gene. Identification of susceptibility genes have clinical impact by reducing disease-associated mortality through improving risk prediction, with the possibility of prevention strategies, and developing new targeted treatments and these clinical implications are also discussed.

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Section: Protein Truncating Variants In Confirmed Susceptibility Gsupporting

confidence: 62%

Section: Protein Truncating Variants In Confirmed Susceptibility Gmentioning

confidence: 99%

Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer

Pavanello

Chan

Ariff

et al. 2020

Cancers

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“…Variants in this genes have been associated with a deficiency in HR and increased sensitivity to DNA damage, classifying BARD1 as a gene of moderate penetrance to BC and OC [23,[77][78][79]. All three associated variants are described as VUS on ClinVar, but p.Asn255Ser (c.764A > G) and p.Lys423Arg (c.1268A > G) lack studies characterizing their effects on protein functions.…”

Section: Discussionmentioning

confidence: 99%

“…With the popularization of next-generation sequencing technologies (NGS), genes encoding proteins that work in the homologous recombination DNA repair pathway (HR), as well as mismatch repair (MMR) pathway, have been frequently reported as mutated in hereditary BC and OC cases [14,16,[20][21][22][23][24][25][26]. Most genes are not only frequently mutated but they have also been considered by NCCN guidelines in the clinical management of patients at risk since they are associated with a high to moderate penetrance of BC and OC [4].…”

Section: Introductionmentioning

confidence: 99%

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population

et al. 2020

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Background: The Hereditary Breast and Ovarian Cancer Syndrome (HBOC) occurs in families with a history of breast/ ovarian cancer, presenting an autosomal dominant inheritance pattern. BRCA1 and BRCA2 are high penetrance genes associated with an increased risk of up to 20-fold for breast and ovarian cancer. However, only 20-30% of HBOC cases present pathogenic variants in those genes, and other DNA repair genes have emerged as increasing the risk for HBOC. In Brazil, variants in ATM, ATR, CHEK2, MLH1, MSH2, MSH6, POLQ, PTEN, and TP53 genes have been reported in up to 7.35% of the studied cases. Here we screened and characterized variants in 21 DNA repair genes in HBOC patients. Methods:We systematically analyzed 708 amplicons encompassing the coding and flanking regions of 21 genes related to DNA repair pathways (ABRAXAS1, ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51, TP53 and UIMC1). A total of 95 individuals with HBOC syndrome clinical suspicion in Southeast Brazil were sequenced, and 25 samples were evaluated for insertions/deletions in BRCA1/BRCA2 genes. Identified variants were assessed in terms of population allele frequency and their functional effects were predicted through in silico algorithms. Results: We identified 80 variants in 19 genes. About 23.4% of the patients presented pathogenic variants in BRCA1, BRCA2 and TP53, a frequency higher than that identified among previous studies in Brazil. We identified a novel variant in ATR, which was predicted as pathogenic by in silico tools. The association analysis revealed 13 missense variants in ABRAXAS1, BARD1, BRCA2, CHEK2, CDH1, MLH1, PALB2, and PMS2 genes, as significantly associated with increased risk to HBOC, and the patients carrying those variants did not present large insertions or deletions in BRCA1/BRCA2 genes.

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“…Based on the clinical characteristics of the latter group, mutations in genes other than BRCA1/2 seemed to confer a high risk of cancer development, indicating that a wider gene analysis could improve protocols of surveillance [43]. A very recent work by Suszynska et al [44] showed the results of a large meta-analysis based on results obtained from multi-gene panel testing. After evaluating 37 genes usually analyzed in BC/OC predisposition, the authors highlighted several non-BRCA genes associated with higher breast/ovarian cancer risk, providing evidence on the possibility of identifying groups of genes more specifically connected to BC/OC.…”

Section: Gene-panel Sequencing Approach In Familial Non-brca Breast/omentioning

confidence: 99%

Applications of Next Generation Sequencing to the Analysis of Familial Breast/Ovarian Cancer

et al. 2020

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Next generation sequencing (NGS) provides a powerful tool in the field of medical genetics, allowing one to perform multi-gene analysis and to sequence entire exomes (WES), transcriptomes or genomes (WGS). The generated high-throughput data are particularly suitable for enhancing the understanding of the genetic bases of complex, multi-gene diseases, such as cancer. Among the various types of tumors, those with a familial predisposition are of great interest for the isolation of novel genes or gene variants, detectable at the germline level and involved in cancer pathogenesis. The identification of novel genetic factors would have great translational value, helping clinicians in defining risk and prevention strategies. In this regard, it is known that the majority of breast/ovarian cases with familial predisposition, lacking variants in the highly penetrant BRCA1 and BRCA2 genes (non-BRCA), remains unexplained, although several less penetrant genes (e.g., ATM, PALB2) have been identified. In this scenario, NGS technologies offer a powerful tool for the discovery of novel factors involved in familial breast/ovarian cancer. In this review, we summarize and discuss the state of the art applications of NGS gene panels, WES and WGS in the context of familial breast/ovarian cancer.

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Large-scale meta-analysis of mutations identified in panels of breast/ovarian cancer-related genes — Providing evidence of cancer predisposition genes

Cited by 52 publications

References 39 publications

Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer

Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population

Applications of Next Generation Sequencing to the Analysis of Familial Breast/Ovarian Cancer

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